下一代测序技术引领下的血液系统恶性肿瘤研究新进展：第55届美国血液学会年会报道

第55届美国血液学会（ASH）年会最大亮点是在下一代测序技术（NGS）引领下,血液系统恶性肿瘤诊断、发病机制、疗效评价、预后分析和微小残留病（MRD）监测等领域出现一系列革命性进步.文章仅将第55届Best ASH中应用NGS技术取得重要突破的7篇论文介绍给国内读者.     

Standardized decision support in next generation sequencing reports of somatic cancer variants

Of hundreds to thousands of somatic mutations that exist in each cancer genome, a large number are unique and non‐recurrent variants. Prioritizing genetic variants identified via next generation sequencing technologies remains a major challenge. Many such variants occur in tumor genes that have well‐established biological and clinical relevance and are putative targets of molecular therapy, however, most variants are still of unknown significance. With large amounts of data being generated as high throughput sequencing assays enter the clinical realm, there is a growing need to better communicate relevant findings in a timely manner while remaining cognizant of the potential consequences of misuse or overinterpretation of genomic information. Herein we describe a systematic framework for variant annotation and prioritization, and we propose a structured molecular pathology report using standardized terminology in order to best inform oncology clinical practice. We hope that our experience developing a comprehensive knowledge database of emerging predictive markers matched to targeted therapies will help other institutions implement similar programs.     

Feasibility of real time next generation sequencing of cancer genes linked to drug response: Results from a clinical trial

The successes of targeted drugs with companion predictive biomarkers and the technological advances in gene sequencing have generated enthusiasm for evaluating personalized cancer medicine strategies using genomic profiling. We assessed the feasibility of incorporating real‐time analysis of somatic mutations within exons of 19 genes into patient management. Blood, tumor biopsy and archived tumor samples were collected from 50 patients recruited from four cancer centers. Samples were analyzed using three technologies: targeted exon sequencing using Pacific Biosciences PacBio RS, multiplex somatic mutation genotyping using Sequenom MassARRAY and Sanger sequencing. An expert panel reviewed results prior to reporting to clinicians. A clinical laboratory verified actionable mutations. Fifty patients were recruited. Nineteen actionable mutations were identified in 16 (32%) patients. Across technologies, results were in agreement in 100% of biopsy specimens and 95% of archival specimens. Profiling results from paired archival/biopsy specimens were concordant in 30/34 (88%) patients. We demonstrated that the use of next generation sequencing for real‐time genomic profiling in advanced cancer patients is feasible. Additionally, actionable mutations identified in this study were relatively stable between archival and biopsy samples, implying that cancer mutations that are good predictors of drug response may remain constant across clinical stages.     

二代测序技术在成熟淋巴肿瘤研究中的应用进展:第57届美国血液学会年会报道

二代测序技术近年来逐渐开始应用于成熟淋巴肿瘤的科学研究和临床实践.第57届美国血液学会(ASH)年会报道了多项二代测序技术在淋巴肿瘤发病机制研究、临床治疗、预后评估和耐药机制研究中的应用.文章选取有代表性的报道,总结二代测序技术在成熟淋巴肿瘤研究中的应用进展.     

二代测序技术在血液肿瘤研究中的应用进展:第56届美国血液学会年会报道

与上届会议相比,第56届美国血液学会(ASH)年会增加了更多的二代测序技术对血液系统疾病的研究,包括疾病的诊断和分型、危险度分层、微小残留病(MRD)的检测、克隆演变、预后以及指导治疗.主要选取几篇具有代表性的文章,概述二代测序技术在血液病研究中的应用进展.     

Structural variation discovery in the cancer genome using next generation sequencing: Computational solutions and perspectives

Somatic Structural Variations (SVs) are a complex collection of chromosomal mutations that could directly contribute to carcinogenesis. Next Generation Sequencing (NGS) technology has emerged as the primary means of interrogating the SVs of the cancer genome in recent investigations. Sophisticated computational methods are required to accurately identify the SV events and delineate their breakpoints from the massive amounts of reads generated by a NGS experiment. In this review, we provide an overview of current analytic tools used for SV detection in NGS-based cancer studies. We summarize the features of common SV groups and the primary types of NGS signatures that can be used in SV detection methods. We discuss the principles and key similarities and differences of existing computational programs and comment on unresolved issues related to this research field. The aim of this article is to provide a practical guide of relevant concepts, computational methods, software tools and important factors for analyzing and interpreting NGS data for the detection of SVs in the cancer genome.     

Ovarian metastasis from lung adenocarcinoma with ALK-positive rearrangement detected by next generation sequencing: A case report and literatures review

Ovarian metastasis is an exceptionally rare condition in lung adenocarcinoma patients and is often difficult to distinguish from primary ovarian carcinoma. ALK (anaplastic lymphoma kinase) tyrosine kinase inhibitors elicit a significant objective response rate and are well-tolerated in advanced ALK-positive lung cancer. Hence, we report a case of a 41-year-old woman with ovarian metastases from NSCLC. After receiving a 6 course first line chemotherapy and 8 course maintenance therapy, the patient suffered acute abdominal pain, so surgery was performed. ALK rearrangement was detected by next generation sequencing, with a 13% abundance of ALK fusion. Crizotinib was administered, and the disease remained stable after 10 months of crizotinib therapy. Further, we reviewed the literature related to characteristics of metastatic ovarian malignancies that form from lung tumors, the utility of ALK inhibition for treating ALK-positive NSCLC, the molecular diagnosis of ALK rearrangement and the role of next generation sequencing for ALK rearrangement detection.     

Computational methods for detecting copy number variations in cancer genome using next generation sequencing: principles and challenges

Accurate detection of somatic copy number variations (CNVs) is an essential part of cancer genome analysis, and plays an important role in oncotarget identifications. Next generation sequencing (NGS) holds the promise to revolutionize somatic CNV detection. In this review, we provide an overview of current analytic tools used for CNV detection in NGS-based cancer studies. We summarize the NGS data types used for CNV detection, decipher the principles for data preprocessing, segmentation, and interpretation, and discuss the challenges in somatic CNV detection. This review aims to provide a guide to the analytic tools used in NGS-based cancer CNV studies, and to discuss the important factors that researchers need to consider when analyzing NGS data for somatic CNV detections.     

Clinical next generation sequencing to identify actionable aberrations in a phase I program

Purpose

We determined the frequency of recurrent hotspot mutations in 46 cancer-related genes across tumor histologies in patients with advanced cancer.

Methods

We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA).

Results

Of the 500 patients, 362 had at least one reported mutation/variant. The most common likely somatic mutations were within TP53 (36%), KRAS (11%), and PIK3CA (9%) genes. Sarcoma (20%) and kidney (30%) had the lowest proportion of likely somatic mutations detected, while pancreas (100%), colorectal (89%), melanoma (86%), and endometrial (75%) had the highest. There was high concordance in 62 patients with paired primary tumors and metastases analyzed. 151 (30%) patients had alterations in potentially actionable genes. 37 tumor types were enrolled; both rare actionable mutations in common tumor types and actionable mutations in rare tumor types were identified.

Conclusion

Multiplex testing in the CLIA environment facilitates genomic characterization across multiple tumor lineages and identification of novel opportunities for genotype-driven trials.     

Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management

Background

Next generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour.

New Era of Personalized Medicine: A 10‐Year Anniversary

This letter comments on progress since the publication 10 years ago of the article by Langreth and Waldholz announcing a new era in personalized medicine.     

Afatinib treatment for her-2 amplified metastatic colorectal cancer based on patient-derived xenograft models and next generation sequencing

Background: Substantial progress has been made in metastatic colorectal cancer (mCRC) treatment, but there is still a fraction of patients cannot find any effective therapeutic strategy after guideline-recommended standard chemotherapy and molecular targeted therapy.

Case presentation: Here we present a KRAS/NRAS/BRAF wild-type mCRC patient who has been previously treated with FOLFIRI (fluorouracil, leucovorin, and irinotecan), XELOX (capecitabine and oxaliplatin), cetuximab and bevacizumab, and then received the next generation sequencing (NGS) and whose metastatic subcutaneous nodule was resected to generate patient-derived xenograft (PDX) models. The NGS revealed HER-2 amplification as well as an activating mutation S310F and PDX models tested several drugs finding that afatinib was the optimal agent with notable efficacy and well tolerance among 6 regimens. Therefore, this patient started to take afatinib orally and achieved 3 months progression-free survival (PFS) and relief of clinical symptoms without severe adverse effects.

Conclusions: NGS and PDX models have great significance for precision and individualized medicine in the mCRC treatment, especially for patients whose diseases have been progressed after multiline standard therapies.